To reach the National Cancer Institute's goal of reducing cancer mortality 50% by the year 2000, significant progress will have to be made in the prevention of lung cancer, the leading cause of U.S. cancer mortality among both men and women. However, even among individuals with chronic environmental exposures, such as long term cigarette smoking, the risk of lung cancer is relatively low. Preliminary studies suggest that this risk is unevenly distributed, with certain individuals and families having much greater risks of lung cancer development. Such clustering in families suggests that genetic susceptibility may be a factor in carcinogenesis. Previous studies have identified a number of genes that may influence susceptibility to lung cancer. These loci are felt to mediate lung cancer risk through the detoxification of (or failure to detoxify) common environmental agents such as cigarette smoke. The primary goal of this study is to relate lung cancer susceptibility in individuals and families to DNA based variation among selected candidate detoxification loci. The study will identify new DNA-based variation in an extended collection of detoxification genes which may mediate the carcinogenic effects of exogenous and endogenous lung cancer-related exposures. This variation will be developed into assays that permit high-throughput characterization. Once identified, tests for association of variation in candidate loci in cases when compared to sex-matched controls who are smokers and non-smokers, will be conducted. Assessment of association dependent on case characteristics will be made. Using the family history information obtained from each case and control reference individual, the patterns of cancer aggregation in families will be assessed. Finally, the relationship between aggregation with families and variation of candidate genes in probands and their family members will be determined.